Twenty-six million adults in the US are affected by chronic kidney disease (CKD) including more than 400,000 individuals with end-stage renal disease (ESRD), and more than half are elderly (e65 years). Cognitive impairment is also common among elderly individuals and associated with higher morbidity and mortality. Yet the nature and long term course of cognitive decline among those with CKD, especially as they transition to ESRD is virtually unknown. The NIDDK- sponsored Chronic Renal Insufficiency Cohort (CRIC) study, which follows a large cohort of adults with CKD through the transition to ESRD, presents a unique opportunity to address this critical gap in knowledge. Our ongoing work in CRIC is characterizing cognitive function in CKD prior to the development of ESRD. In this application, a competitive renewal of R01-DK069406, we plan to investigate cognitive trajectories of individuals transitioning from advanced CKD to ESRD. First, we will leverage our prior work in CRIC in order to investigate the long term (6-8 year) course of cognitive decline among 3000 adults with CKD and to determine how this course affects management of CKD and geriatric outcomes including timing of dialysis, catheter use and risk of mortality and frailty. In addition, we propose to conduct semi-annual telephone cognitive assessments among approximately 420 participants with advanced CKD in order to characterize cognitive trajectory during the CKD-ESRD transition. We will also measure several biomarkers associated with advanced CKD that may also be linked with cognitive decline such as markers of oxidative stress, cystatin-c, anemia and advanced glycated end products. We hypothesize that trajectory of cognitive decline accelerates at the onset of ESRD, that dialysis initiation influences cognitive decline in vulnerable individuals, and that selected biomarkers associated with advanced CKD identify individuals at high risk for decline. Results stemming from this proposal will be critical for assessing the risks and benefits of dialysis in older adults, for determining natural course of cognitive function among those with CKD, and for devising effective prevention and management strategies for cognitive decline in this population. We have assembled an outstanding group of investigators from a variety of disciplines with a track record of productive collaboration and dedication who will address these important and innovative aims.